SHHactivated

SHHactivated refers to the cellular signaling state in which the Sonic Hedgehog (SHH) pathway is active. The pathway begins when SHH ligand binds the PTCH1 receptor, releasing inhibition of the SMO protein. Activated SMO initiates a signaling cascade that modulates GLI transcription factors (GLI1, GLI2, GLI3), leading to the transcription of target genes, including GLI1 and PTCH1, and driving cellular programs related to proliferation and survival.

In development, SHH signaling shapes tissue patterning and organ formation, influencing neural tube patterning, limb development, and other processes. In adults, SHH activity helps maintain certain stem cell populations and tissue homeostasis. Aberrant SHH activation is associated with various diseases, most notably cancers such as basal cell carcinoma and medulloblastoma, and has also been observed in pancreatic and lung cancers. Mechanisms of dysregulation include overexpression of SHH ligand, mutations in PTCH1 or SMO that relieve repression or constitutive activation, and loss of SUFU, a negative regulator of GLI activity. Because SHH activation can drive tumor growth and maintenance, it can serve as a biomarker for disease classification and as a target for therapy.

Detection and treatment approaches focus on measuring pathway activity and inhibiting signaling. Pathway activity can be assessed by elevated expression of GLI1 or PTCH1, or by GLI1 protein visualization in tissue samples. Therapeutically, SMO inhibitors such as vismodegib and sonidegib have been used to treat SHH-driven tumors, with ongoing development of downstream GLI inhibitors and combination strategies to overcome resistance. Resistance may arise from SMO mutations, GLI2 amplification, or SUFU loss, necessitating alternative therapeutic approaches.